Citation Manager Formats

Share

Abstract

Background: The authors identified the second known mutation in the α-synuclein(SNCA) gene, an alanine-to-proline exchange in amino acid position 30 (A30P), that cosegregates with the disease in one German family with autosomal dominantly inherited parkinsonism (ADP). The authors studied carriers of the A30P mutation to compare the phenotype of this mutation with idiopathic PD (IPD) and to assess nigrostriatal dopaminergic function in symptomatic and preclinical mutation carriers.

Methods: The pedigree of the A30P family spans five generations with five affected individuals. The authors performed detailed neurologic examinations followed by mutation analysis in 11 living individuals. In three mutation carriers, two individuals with definite PD and one person at risk for PD, they used l-[18]F-fluoro-3,4-dihydroxyphenylalanine (F-DOPA), [11]C-raclopride (RAC), and [18]F-fluorodeoxyglucose (FDG) PET to investigate presynaptic dopaminergic function, dopamine D2 receptors, and cerebral energy metabolism. The authors studied the cognitive functions of carriers of the A30P mutation using neuropsychological screening.

Results: PET studies revealed striatal presynaptic dopaminergic alterations consistent with sporadic IPD in two affected family members and no evidence for nigrostriatal dopaminergic dysfunction in one presymptomatic mutation carrier. Neuropsychological testing in four mutation carriers provided evidence for cognitive impairment as a frequent and early symptom of the A30P mutation; this is also supported by regional cerebral energy metabolism alterations in the clinically presymptomatic subject.

Conclusions: The phenotype of the A30P mutation in the SNCA gene is similar to that of sporadic IPD, including a high variability of the age at disease onset, ranging from 54 to 76 years. The follow-up of presymptomatic carriers of the A30P mutation may give insight into preclinical disease stages and early manifestations of PD.

The majority of PD cases are sporadic as defined by the absence of a family history for PD. However, the description of large families with apparently autosomal dominant inherited parkinsonism (ADP) prompted the investigation of genetic factors in the pathogenesis of PD.1-3⇓⇓ In 1996, Polymeropoulos et al. mapped the first locus responsible for autosomal dominantly inherited parkinsonism (PARK1) to chromosome 4q21-23 in a large Italian (Contursi) kindred.4,5⇓ Subsequently, an A53T mutation in the α-synuclein(SNCA) gene was identified as the cause of ADP in this family, and was also found in five additional Greek families.6,7⇓ Extensive trade and cultural exchange in ancient times between Southern Italy and Greece strongly points to a common ancestor of these families,4-7⇓⇓⇓ reflecting a founder effect for the A53T mutation. Several studies excluded the A53T mutation in a large number of patients with familial parkinsonism and sporadic PD.8-10⇓⇓ Recently, we identified a second mutation, an alanine-to-proline exchange in amino acid position 30 of the SNCA protein, as being responsible for ADP in one German family.11 This mutation affects a region that is highly conserved among all examined species. Biochemical studies give further evidence for a pathogenic role of the A53T and A30P mutations in the SNCA gene. Mutated forms of the SNCA protein are more prone to aggregate and form fibrils.12,13⇓ Moreover, SNCA carrying the A30P mutation is devoid of vesicle-binding activity.14 Thus mutations in the SNCA gene are responsible for some rare forms of ADP.

The clinical characteristics of individuals carrying the A53T mutation in the SNCA gene have been described.4,7⇓ The phenotype shows typical features of IPD including the cardinal features (rigidity, hypokinesia, postural instability, and resting tremor) and a positive response to l-dopa therapy. Compared with sporadic idiopathic PD (IPD), disease onset in A53T carriers occurs relatively early in life, and the course from disease onset to death is rapid. We characterized the phenotype of the second known mutation in ADP. To compare biochemical changes in brains of A30P mutation carriers with those observed in patients with sporadic IPD, and to identify a possible impairment of the dopamine metabolism in presymptomatic mutation carriers, we performed PET studies in A30P carriers. Detailed neuropsychological screening was performed to assess cognitive functions of mutation carriers. To characterize genetic factors possibly influencing the clinical expression of the disease, we performed genotyping for polymorphisms in the APOE and ubiquitin C-terminal hydrolase (UCHL1) gene in all living individuals carrying the A30P mutation.

Patients and methods.

Genealogic investigation.

The genealogic investigation of the pedigree included personal interviews and detailed neurologic examination of 11 individuals. Information on other family members was obtained from medical records, historical documents, telephone interviews, and records from the eldest living family members. All clinical evaluations were performed by neurologists of the Department of Neurology, Ruhr-University Bochum, who are experienced in the diagnosis of movement disorders. Examination was carried out before genotyping each individual. PD was diagnosed according to the UK PD Society Brain Bank (UKPDSBB) criteria.15 All individuals gave informed consent. Ethical approval was obtained by the Ethics Committee of the Ruhr-University Bochum. For the deceased mother of our index patient, we refer to reports from family members and medical records confirming the diagnosis of PD. For other deceased individuals without medical records, we accepted convincing and consistent reports of the cardinal features of PD from different family members. Four mutation carriers were followed up for 2 years and were examined at least twice during this period. We performed a rating of motor performance under medication and also after at least 12 hours without dopaminergic medication using the Unified PD Rating Scale (UPDRS; subset III).16

Mutation analysis.

After informed consent, DNA from 11 individuals was genotyped. Screening for the A30P mutation in the SNCA gene was performed as described.11

APOE and ubiquitin C-terminal hydrolase genotyping.

The genotyping of 11 family members for the APOE polymorphism and the S18Y polymorphism in the UCHL1 gene was performed as described elsewhere.17,18⇓

PET studies.

In all three mutation carriers of generation IV ( figure 1), PET studies were performed to assess a possible metabolic impairment affecting the brain. At the time of investigation, two of the mutation carriers presented with definite PD according to the UKPDSBB criteria and one individual was at risk to develop parkinsonism. In our study, we used three different tracers: 1) l-[18]F-fluoro-3,4-dihydroxyphenylalanine (F-DOPA), which is an analogue of levodopa and can be used as a tracer for l-dopa transport from blood to brain, dopamine formation, and subsequent conversion into metabolites; 2) [11]C-raclopride (RAC), which is a compound specific for dopamine D2 receptor binding, allowing an in vivo quantitative analysis of receptor binding in striatum; and 3) [18]F-fluorodeoxyglucose (FDG), which is a tracer that reflects the cerebral energy metabolism. All PET studies were performed and evaluated at the Groningen University Hospital (Academisch Ziekenhuis Groningen, the Netherlands), using a Siemens ECAT Exact HR + scanner (Siemens, Erlangen, Germany). Subjects were positioned with their head in the scanner using a laser beam for accurate positioning and head fixation. The patients had not been taking their regular medications for at least 12 hours prior to the performance of the scanning. The three tracers listed above were applied during three scanning sessions on separate days. Before the F-DOPA and RAC emission scans, a 30-minute transmission scan was performed for correction of signal attenuation in tissue. A mean of 194 MBq F-DOPA was injected IV over 1 minute with a constant volume infusion pump. One hour before administration, all subjects were premedicated with 2 mg/kg carbidopa orally to reduce peripheral decarboxylation. The scanning protocol consisted of 21 time frames with a total scan duration of 120 minutes according to the following protocol: 10 × 30 seconds, 3 × 300 seconds, 4 × 600 seconds, and 4 × 900 seconds. One hundred ten and 196 MBq of RAC (for technical reasons no RAC scan could be performed in Patient IV-5) were injected IV over a period of 1 minute. Scanning began at the start of tracer infusion and consisted of 17 time frames with a total duration of 60 minutes according to the following protocol: 10 × 30 seconds, 3 × 300 seconds, and 4 × 600 seconds. A mean of 198 MBq FDG was injected IV 30 minutes before a static emission scan of 30 minutes’ duration was performed.

Figure 1. Pedigree of the A30P family. Black signs indicate clinically affected individuals according to the United Kingdom PD Society Brain Bank criteria. Gray signs indicate individuals with only discrete/variable neurologic symptoms. For carriers of the A30P mutation in the α-synuclein(SNCA) gene, the results of genotyping for the APOE (ε3 or ε4 alleles) and ubiquitin C-terminal hydrolase (S: serine, Y: tyrosine) polymorphisms are indicated next to the respective individual. Living individuals are masked for sex. In generations IV and V, additional individuals have been introduced or omitted for reasons of confidentiality.

Early time frames in the F-DOPA and RAC studies were integrated to form images of flow distribution. This was used to determine linear realignment parameters to transform the dynamic data set to Talairach stereotactic space. A region of interest (ROI) template was used to determine four striatal and one occipital ROI. Kocc values were estimated for the F-DOPA study on a pixel-by-pixel basis.19 The binding potentials (BP) from the RAC study were estimated using the reference tissue model.20 For the caudate nucleus and putamen, the slices presenting the highest values were taken. For FDG-PET, 14 anatomical ROI were localized in Talairach stereotactic space using linear spatial normalization of the data and a standard template. Standard uptake values of local to cerebellar mean were calculated for each region. A group of seven healthy persons (three men and four women, mean age 76 ± 6.4 SD years) underwent F-DOPA and a group of six subjects (two men and four women, mean age 75 ± 6.6 SD years) underwent FDG-PET scans following the procedure described above. For RAC uptake values, values from the literature were taken as comparison.21,22⇓

Neuropsychological testing.

A comprehensive neuropsychological battery aimed at intelligence, frontal brain functioning, memory and attention, construction, and visual perception was administered to describe in detail the cognitive profile of carriers of the A30P mutation in the SNCA gene.

Intelligence was assessed with a shortened version of the Wechsler Adult Intelligence Scale (WAIS), which includes the Information, Similarities, Picture Completion, and Block Design subtests.23 A German adaptation of the Benton Word fluency task, which represents literal word fluency, was used to measure frontal functioning.24 The Digit Span forward and backward and the Wechsler Memory Scale (WMS) Logical Memory and the delayed reproduction of the Rey Figure were used to test verbal and visual memory. Copying of the Rey Figure was included as a task sensitive to visuo-constructional problems. We used the scoring system presented by Canavan and Sartory25 (1990), with a maximum score of 47 for each the immediate and delayed condition. The performance of the four ADP patients on this task was compared with the performance of 12 healthy controls (seven women and five men) with an age range of 55 to 75 years (mean 68.8; SD 7.7) and mean formal education of 9.1 years (SD 2.1). Constructional abilities and executive functioning were further assessed with the Clock Drawing test.26 The Visual Object and Space Perception battery was given to assess visuo-perceptual and spatial abilities.27

Results.

General.

The A30P family is of German origin dating back to the 19th century. The pedigree comprises five generations (see figure 1). The disease phenotype of clinically affected individuals carrying the A30P mutation in the SNCA gene reflects IPD, including the cardinal features muscular rigidity, tremor, bradykinesia, and postural instability ( table 1). In the pedigree (see figure 1), we identified five affected individuals (two men, three women) and two individuals (one man, one woman) with only subtle neurologic disturbances. The age at disease onset varied from 54 years in Individual IV-3 to 76 years in Individual III-9. Screening 11 living members of the family for the A30P mutation in the SNCA gene, we identified five mutation carriers, three of them presenting with definite PD according to the UKPDSBB criteria.

Clinical characteristics of affected individuals and individuals at risk to develop PD in the A30P family

Selected case reports according to the pedigree.

Individual I-2.

This subject, born in 1869, had PD as judged by the family. Consistently, grandchildren reported resting tremor of the head and slowing of movements. The disease onset could not be determined reliably, but symptoms were already present before the age of 60. Death occurred at age 63 after appendectomy.

Individual II-1.

Born in 1883, Individual II-1 died at age 53 from a “heart attack” according to records of his children. Problems with cardiac function resulted in dispense from military service. Until his death, no movement abnormalities were reported.

Individual III-3.

The mother of our index patient was born in 1914 and died bed-bound in 1974 owing to complications of PD according to familial records. Consistent information about initial movement abnormalities was reported when she was 54. Her children observed tremor of both hands. Later a shuffling gait, rigidity of upper and lower extremities (more pronounced on the right hand side), and hypophonia developed gradually. Medical records from 1972 confirm the diagnosis PD and report on motor fluctuations during antiparkinsonian therapy.

Individual III-9.

This subject was born in 1923. She had a cardiac infarction at age 70. Her neurologic history was unremarkable except for claiming slight cognitive problems since 1993. She was examined twice during a 20-month period. On the occasion of the first neurologic examination in 1998, she presented with discrete resting tremor of both hands and postural instability not fulfilling the diagnostic criteria for PD. The symptoms had already been observed for several years, but did not interfere with activities of daily living. In 1999, we observed additional slight rigidity in both arms and a mild slowing and reduction in amplitude during rapid alterning movements of hands more pronounced on the left hand side (Hoehn and Yahr stage 2.5).28 Therefore, owing to the clinical course, a diagnosis of definite PD can be made according to the UKPDSBB criteria.

Individual IV-3.

The 65-year-old index patient of the family first presented to our department in 1993. At this time, a positive family history for PD was reported because the patient’s mother (III-3) was affected. He observed first symptoms of PD in 1988 at age 54, when his gait became shuffling and movements slowed down, more pronounced on the left-hand side. Treatment with levodopa/carbidopa began in 1988 with an excellent response. In 1990, difficulties in writing and deterioration of motor functions resulted in retirement. First motor fluctuations (“on”/”off’ periods) were observed in 1993. Brain CT scans were not remarkable. In 1998, first visual hallucinations with insight retained were observed under levodopa therapy and “off” periods became more frequent. Since 1999, the index patient has presented with severe disability and excessive salivation corresponding to Hoehn and Yahr stage 4; speech is severely affected, “off” periods take up to 50% of the waking day, and occasional hallucinations without insight are experienced.

Individual IV-5.

The younger sibling of our index patient was born in 1942. At the first neurologic examination in 1997 in our department, an impaired motoric capacity of the right arm was reported. PD was not diagnosed before. The examination revealed hypomimia, rigidity of the right arm, and slow alternating movements with reduced amplitudes at the right hand (Hoehn and Yahr stage 1). MRI of the brain showed no pathologic alterations. The symptoms responded excellently to dopaminergic therapy. On the latest examination in 1999 no additional symptoms were observed.

Individual IV-6.

At the first neurologic examination in 1997 this 52-year-old individual reported migraine, mild forgetfulness, and rare episodes of shaking of the left leg. These occurred up to four times during the previous 3 years for less than 1 day without apparent progression. The neurologic examinations were normal, except for slight bradydiadochokinesia of the left arm (Individual I-6 is right handed) without any signs of rigidity or resting tremor. Brain MRI showed discrete white matter lesions that may relate to recently diagnosed hypertension. A follow-up examination in 1998 yielded the same results. At the latest neurologic investigation, slight and variable bilateral rigidity of the upper and lower extremities was also observed. To date, this patient’s neurologic disturbances do not fulfill the diagnostic criteria for PD.

Individual V-1.

This individual presented at age 33 with discrete reduction of amplitude during rapid alterning movements of the left arm. No further evidence for a movement disorder was obvious.

PET scan results.

The tracer uptake values of F-DOPA and FDG of the three patients and controls are listed in ⇓ tables 2 and 3. In our index patient (IV-3), F-DOPA uptake into the caudate nucleus and putamen was markedly decreased, as seen in advanced PD. In Patient IV-3, FDG-PET showed striatal hypometabolism, which was more pronounced in the caudate nucleus than in the putamen. Hypometabolism was also observed in the frontal, parietal, and left temporal cortex. The cortical metabolic defects correspond well with the neuropsychological findings in this patient—impairments in frontal tasks, memory function, and constructional abilities. The RAC BP in both putamina (left 1.95, right 1.99) was normal and somewhat lower in the caudate nucleus (left 1.35, right 1.58) compared with published figures.22,23⇓

Individual IV-5 also revealed a marked decrease of the F-DOPA uptake into both striata. This was more pronounced on the left-hand side in correspondence with the clinical findings. The FDG-PET showed essentially a normal distribution of the energy metabolism in the brain.

For Individual IV-6, the F-DOPA and RAC uptake was normal in both striata. The FDG-PET showed no pathologic changes except for a decreased tracer uptake in the left temporal cortex and an indication of lower metabolism in the left frontal medial cortex and left caudate nucleus.

Neuropsychological testing.

Table 4 summarizes measures of intelligence, frontal brain functioning, attention and memory, construction, and visual perception of four individuals carrying the A30P mutation. Patient IV-3 was unable to perform the IQ task, which indicates a substantial degree of cognitive decline in this person. In the word fluency task, a measure of left frontal functioning, family members IV-6, III-9, and IV-3 showed severe deficits. Assessing verbal memory using the Digit Span task, Individual IV-6 was impaired in both the forward and backward condition, whereas Individual IV-3 was only significantly impaired in the backward condition. On the Logical Memory task, three individuals (IV-6, III-9, and IV-3) showed severe impairments in the immediate recall and impaired or borderline performance in the delayed recall condition. Visual memory was also severely impaired in family members IV-6, III-9, and IV-3. On constructional abilities, Patients III-9 and IV-3 performed significantly below controls. Individual IV-6 was significantly impaired in the immediate reproduction of the Rey Figure and showed a borderline impairment on the Clock Drawing test. Patient IV-5 was unimpaired on Clock Drawing test and presented a borderline impairment on the Rey Figure test. Visuo-perceptual and spatial abilities as assessed by the Visual Object and Space Perception battery were severely impaired only in Patient IV-3, whereas Individuals IV-5, IV-6, and III-9 showed no deficits. In summary, patients in the early stages of ADP (Patients IV-5 and III-9) and one individual at risk to develop PD showed a varying pattern of deficits in tests assessing frontal functioning, memory, and construction, whereas visuo-perceptual and spatial abilities as well as intelligence were unaffected.

Performance of four carriers of the A30P mutation on standard neuropsychological tests

APOE and UCHL1 genotyping.

The genotypes for APOE and UCHL1 of carriers of the A30P mutation are indicated in the pedigree (see figure 1). Regarding the APOE polymorphism, only two alleles (ε3 and ε4) were present; the ε2 allele was not observed in our family. Genotyping for the S18Y polymorphism in the UCHL1 gene detected both alleles in our family; however, homozygosity for the Tyr18 allele was not found.

Discussion.

To date, seven ADP families are known in which mutations in the SNCA gene cosegregate with the disease: six families carrying the A53T mutation and the family presented here, which is the only one carrying the A30P mutation. The phenotypic characterization of the A30P mutation in the SNCA gene delineates a clinical pattern that is similar to that of sporadic IPD. Because all affected mutation carriers are living, no autopsy material was available to demonstrate the presence of SNCA-positive Lewy bodies (LB) in the substantia nigra. For individuals of the Contursi kindred carrying the A53T mutation, pathologic changes typical for IPD including the presence of LB have been shown.1 The phenotype of the A30P mutation resembles that of the A53T mutation, including the cardinal features of PD and a positive and sustained response to l-dopa therapy, except for the early age at disease onset in individuals carrying the A53T mutation. The mean age at disease onset for the Contursi kindred was 45.6 years (SD: 13.48) and in Family H a tendency for a decreasing age at onset in subsequent generations has been observed, suggesting anticipation.2,4⇓ In the A30P family, however, the mean age at disease onset was 59.7 years (SD: 10.8; range: 54 to 76 years), reflecting the mean age at onset observed in sporadic IPD.29 Owing to the limited information about deceased PD patients’ definite assessments of the disease progression must depend on clinical follow-up investigations of living mutation carriers. Our current data might indicate a milder phenotype caused by the A30P mutation. This clinical observation is supported by in vitro studies investigating the biochemical properties of different mutated SNCA proteins during fibrillogenesis, the possible key step in protein aggregation involved in neurodegeneration in PD. The authors found mutant protein containing the A53T substitution fibrillizing more rapidly than the A30P mutant form.12,13⇓ This suggests an accelerated disease progression in A53T mutation carriers, which might be reflected by the earlier age at disease onset.

The striatal presynaptic dopaminergic function and postsynaptic D2 receptor binding in carriers of the A30P F-DOPA uptake was reduced in the striata of both affected individuals, as seen in patients with sporadic IPD. In the putamen of the index case, IV-3, tracer uptake (Kocc) was on average reduced to 38% of normal values, identical to the reduction in caudate nucleus. In the other affected patient (IV-5) the mean reduction of uptake was to 29% of control values in the putamen and to 54% in the caudate nucleus. This finding is consistent with the abnormal distribution pattern observed in patients with sporadic IPD ( figure 2). A recent PET study in four affected individuals of Family H carrying the A53T mutation gave similar results.30 In our PET study, we included one individual at risk (IV-6)—that is, younger than the expected age at disease onset in the family—to investigate early metabolic changes in the brain of mutation carriers. A PET study in familial parkinsonism with unknown genetic status showed abnormally reduced putamen uptake of F-DOPA in eight (25%) asymptomatic relatives of patients with PD. Three of them became symptomatic within 4 years of their scan, giving evidence that reduced striatal F-DOPA uptake may reflect presymptomatic PD.31 However, we demonstrate normal F-DOPA uptake and RAC binding in Individual IV-6 (see figure 2). In patients with early sporadic IPD, an increase of RAC binding can be expected. This suggests that clinical parkinsonism is not imminent in this case. Therefore, this subject needs to be followed up, both clinically and with imaging, in order to assess the value of striatal receptor status in the progression of the disease in terms of presynaptic dopaminergic defect and clinical symptoms. At her last clinical examination (10 months after PET scanning), Subject IV-6 had slight and variable bilateral rigidity of the upper and lower extremities, which might indicate progression of symptoms. However, to date the clinical symptoms do not fulfill the diagnostic criteria for PD.

Figure 2. F-DOPA PET of three mutation carriers and one patient with sporadic PD. F-DOPA uptake in the striata of both affected individuals (IV-3 and IV-4) is reduced as seen in sporadic PD. Normal F-DOPA uptake in one presymptomatic carrier of the A30P mutation (IV-6) is also shown.

Because Individual IV-6 reported memory deficits for several years and because SNCA has been implicated in the pathogenesis of dementia such as AD and dementia with Lewy bodies (DLB),32-34⇓⇓ we performed detailed neuropsychological testing to delineate possible effects of the A30P mutation towards cognitive functions. All examined mutation carriers exhibit deficits in visuo-constructive functions. This is a neuropsychological profile typically present in patients with sporadic IPD. As expected, the severely affected index patient (IV-3), showing the highest degree of cognitive impairment, exhibits the most marked hypometabolism in various cortical regions using FDG-PET. Striatal hypometabolism was also found; this is in agreement with recent findings as described in advanced cases of PD without dementia.35 A previous communication also showed cortical hypometabolism in patients with PD who were also affected at a cognitive level.36 In contrast to the clinically advanced case described here (IV-3), early and mildly affected patients with IPD showed striatal hypermetabolism.37 Interestingly, Individual IV-6 shows at a preclinical stage of PD already marked alterations of cognitive functions, supported by regional cerebral metabolism alterations. This may relate to some other pathology than PD, which might be reflected by discrete white matter lesions in MRI. However, our results are in line with recent findings in first-degree relatives of patients with familial parkinsonism, identifying a subgroup with cognitive impairment comparable with typical PD. The authors postulate that cognitive deficits may precede motor symptoms and therefore represent a preclinical form of PD.38

The observed high variability of the age at disease onset in the A30P family might be explained by the presence of genetic or environmental susceptibility factors influencing the expression of the disease. In familial AD, an influence of the APOE genotype on the age at onset in carriers of mutations in the amyloid precursor protein (APP) and presenilin-2 gene has been reported.39,40⇓ In PD, there is evidence for the ε4 allele of a certain APOE polymorphism being a susceptibility factor for an earlier age at onset.17,41⇓ Furthermore, one allele of an amino acid polymorphism in the UCHL1 gene (Tyr18) has been identified as a possible protective factor in the pathogenesis of PD.18,42⇓ For APOE no influence of the ε4 allele was found, neither on the age at onset nor on cognitive performances in our family. The Tyr18 allele of the UCHL1 gene was only present in two mutation carriers of the A30P family. Individual IV-6 is not affected at age 52. Interestingly, the age at disease onset in Individual III-9, who also carries the Tyr18 allele, is relatively late at 76 years. Therefore, we cannot exclude a possible protective effect of a UCHL1 variant in our family, indicating the relevance of the analysis of this polymorphism in a larger cohort of patients with familial parkinsonism.

The results of our characterization of the phenotype of the A30P mutation based on clinical examination, functional imaging, and neuropsychological assessment are consistent with IPD. This is important because first reports on individuals carrying the A53T mutation have been interpreted as atypical parkinsonism because of the early age at onset and rapid disease progression. In our study, we identified one mutation carrier without alterations of the striatal dopamine metabolism that is younger than the expected age at onset in our family and already shows cognitive impairment. Future studies offer the possibility to assess the preclinical disease window, initial symptoms, and disease progression of PD in this individual. The fact that mutations in the SNCA gene resemble typical IPD has major implications for new therapeutic approaches. Recently, first animal models for PD have been generated expressing wild-type SNCA and mutated SNCA in vertebrates and invertebrates replicating clinical and pathologic features of PD.43,44⇓

Acknowledgments

Supported by FORUM grant of the Faculty of Medicine of the Ruhr-University Bochum, Germany.

Disputes & Debates: Rapid online correspondence

NOTE: All authors' disclosures must be entered and current in our database before comments can be posted. Enter and update disclosures at http://submit.neurology.org. Exception: replies to comments concerning an article you originally authored do not require updated disclosures.

Stay timely. Submit only on articles published within the last 8 weeks.

Do not be redundant. Read any comments already posted on the article prior to submission.

200 words maximum.

5 references maximum. Reference 1 must be the article on which you are commenting.

5 authors maximum. Exception: replies can include all original authors of the article.

Submitted comments are subject to editing and editor review prior to posting.

I, the first and corresponding author, verify that I have read the contents of the PUBLISHING AGREEMENT form. *

I, the first and corresponding author, verify my disclosures and those of my co-authors are up to date at http://submit.neurology.org. *

Select only one of the three options below: *

I am an Author of this Work, and the Work was prepared on my own time - not as part of my duties as an employee.

I prepared (or cooperated in the preparation of) the Work as part of my duties as an employee, and the Work is, therefore, a "work made for hire", as defined by the United States Copyright Act of 1976, as amended.

I prepared (or participated in the preparation of) the Work as part of my official duties as an officer or employee of the United States Government.

NOTE: All authors, besides the first/corresponding author, must complete a separate Disputes & Debates Submission Form and provide via email to the editorial office before comments can be posted.

CAPTCHA

This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.